This project will examine the effects of chronic ingestion of ethanol by alcohol-preferring (P) rats on the cytoarchitecture of pyramidal and granular cells in the hippocampal formation, and on the chemical and anatomical integrity of the serotonergic afferents which project to this structure from the median raphe. This line of rats shows alcohol-consuming behavior similar to human alcoholism. We will examine the hypothesis that the hippocampal formation degenerates with ethanol ingestion through Golgi-Cox cytoarchitectural methods followed by computerized cytomorphometric analysis. We will examine the hypothesis that the serotonergic afferents to the hippocampal formation will be anatomically damaged or blunted in their chemical responses with chronic alcohol consumption using serotonin immunocytochemistry and neurochemical analysis of serotonin and 5-hydroxyindoleacetic acid with high performance liquid chromatography and electrochemical detection (LCEG). We will also examine the effects of acute low and high dose alcohol injections in the alcohol preferring (P) and non-preferring (NP) lines on serotonin with LCEC for inherent differences in the response of the serotonergic afferents to acute ethanol exposure. The role of corticosterone on hippocampal neuronal integrity and on the anatomical and chemical response of the serotonergic afferents to chronic alcohol will be examined in periodically immobilization-stressed rats using Colgi-Cox neuroanatomy, serotonin immunocytochemistry, and LCEC. The effects of alterations of hippocampal neurons and their serotonergic afferents on synaptic connectivity will be studied with x-ray analytical electron microscopy for ultrastructural localization of serotonergic synapses. With this excellent model for alcohol drinking behavior, we will carry out a longitudinal study to elucidate potential pathological effects of voluntary alcohol ingestion on this important neurological system implicated in the neuropathology of alcoholism.